tbuckley/cabot-search huggingface dataset:
Feasibility and utility of the custom RNA-seq for the identification of therapeutic targets and diagnostic biomarkers in glioma.
Authors: Masamichi Takahashi, Shinji Kohsaka, Koichi Ichimura, Hiroyuki Mano, Yoshitaka Narita
Journal: Journal of Clinical Oncology (2023)

e14029 Background: The detection of novel therapeutic targets is increasingly important in oncology. The Todai OncoPanel (TOP) RNA panel is a custom target RNA-seq using the junction capture method to maximize the sensitivity in detecting of known 456 fusion gene transcripts, which is scheduled to be approved for clinical application in Japan in April 2023. Above, TOP RNA panel interrogates aberrantly spliced transcripts and analyzes the expression profiles of 1,390 genes. Malignant brain tumors, including gliomas, require various molecular profiles to be classified based on the latest WHO classification criteria, while their poor prognosis also necessitates new therapeutic targets. In this study, we aimed to classify gliomas and identify the molecular targets by TOP RNA panel. Methods: Among 131 frozen tumor samples of malignant gliomas, 124 samples passed quality control for further validation and were subjected to TOP RNA panel to classify based on the molecular profiles and to identify the molecular targets. Fusion detection and RNA expression analysis were conducted with the original pipeline. Cluster analysis and Gene Set Enrichment Analysis (GSEA) were performed to identify gene sets specific for individual subtypes. Copy numbers of tyrosine kinase genes, MDM2 and CDK4 were evaluated by digital droplet PCR (ddPCR). Results: Among 58 cases of glioblastoma, gene fusions were detected in 11 cases (19.0%) including novel MET fusions, and overexpression of seven tyrosine kinase genes were observed in 21 cases (36.2%). Of the 34 overexpressed genes, gene amplification was observed in 17 genes (50%) by ddPCR. In contrast to IDH-wildtype glioblastoma, IDH-mutant tumors including astrocytomas and oligodendrogliomas hardly harbored fusion genes or gene overexpression. GSEA to compare astrocytomas and oligodendrogliomas identified that the gene sets related to 1p36 and 19q were relatively enriched in astrocytoma, suggesting that regional genomic DNA copy number alterations can be evaluated by gene expression analysis. Conclusions: TOP RNA panel is utilized not only for the detection of molecular targets but also for the molecular classification of glioma, both of which is essential for providing treatments optimized for the individual patients.
A first-in-human study of XTX301, a masked, tumor-activated interleukin-12 (IL-12), in patients with advanced solid tumors.
Authors: John George Knecht, Anurag Gupta, Meghan Duncan, David Crowe, Ekta Patel, Jennifer O'Neil, George Lee, Katarina Luptakova, Martin Gutierrez
Journal: Journal of Clinical Oncology (2023)

TPS2672 Background: Interleukin-12 (IL-12) is a proinflammatory cytokine that has shown promise as an immunotherapy for cancer. Although it has demonstrated potent antitumor activity in mouse models of cancer, development of IL-12 in the clinical setting has been limited by severe toxicities with systemic administration. XTX301 is a half-life extended, masked and tumor-activated IL-12. XTX301 is designed to be pharmacologically inactive in non-tumor tissue when circulating systemically, and unmasked by matrix metalloproteases (MMPs) preferentially active in the tumor microenvironment (TME). The masking domain is engineered to be removed via cleavage at a protease cleavage site in the XTX301 linker by MMPs. XTX301 is designed to produce a localized anti-tumor immune response while limiting exposure of the active form of XTX301 in non-tumor tissue, and thereby improving the therapeutic index of IL-12. Using a murine analog of XTX301 (mXTX301), tumor growth inhibition was demonstrated in vivo in murine models with a single dose of mXTX301. In mouse tumors, mXTX301 stimulated the infiltration of cytotoxic CD8+ T cells and induced pro-inflammatory gene expression signatures. Preclinical data have demonstrated tumor-selective activity of mXTX301 in mice with limited and reversible peripheral toxicities of XTX301 in non-human primates [Malkova et al., AACR 2023]; these data are supportive of further clinical development. Methods: XTX301-01 trial (NCT05684965) is a first-in human, multicenter, Phase 1, open label study to establish the safety and tolerability of monotherapy XTX301, and to determine a recommended phase 2 dose (RP2D). Additional objectives include assessment of pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity and anti-tumor activity of XTX301. The study will enroll patients with solid tumors, including lymphoma, that have locally advanced or metastatic disease and have failed standard therapy, standard therapy does not confer survival benefit, or standard therapy is not available. Patients in part 1A will receive XTX301 monotherapy every 3 weeks via intravenous infusion in an outpatient setting, using a 3+3 dose escalation design. The starting dose for XTX301 is 5 ug/kg. Part 1B will further examine multiple doses of XTX301 as monotherapy in patients with select advanced solid tumors to further characterize PK, PD and dose response relationships. Part 1B will require mandatory fresh tumor biopsies before and after initiation of study drug administration to fully characterize the PD profile and PK of XTX301 in the tumor. Enrollment to the study is planned to begin in the first quarter of 2023. Clinical trial information: NCT05684965 .
The association between body mass index and immune checkpoint inhibitors outcomes in melanoma: Results from real-world data.
Authors: Dina Elantably, Jiasheng Wang, Abdul Rahman Al Armashi, Anas Al Zubaidi, Akram Alkrekshi
Journal: Journal of Clinical Oncology (2023)

e14604 Background: The “obesity paradox” refers to increase cancer risk in obesity with paradoxical improved outcomes. This phenomenon was previously reported in melanoma patients on immunotherapy; however, results are uncertain. Immune checkpoint inhibitors (ICI) are the mainstay of melanoma treatment. There is a lack of real-world data on the impact of body mass index (BMI) on overall survival (OS) and immunotherapy-related adverse events (irAEs) in melanoma patients on ICI. Methods: Data were retrospectively collected from an electronic health record database (TriNetX) which includes over 89 million patients from 56 healthcare systems in the United States. We identified adults with melanoma who received ICI; pembrolizumab, nivolumab, or a combination of ipilimumab and nivolumab between 2012 and 2022. Patients were stratified based on the WHO body mass index (BMI) classification. Overweight and obese patients were 1:1 propensity score-matched for age, sex, race, and use of ICI, with patients with normal BMI. Results: Ourcohort included 11,656 melanoma patients on ICI. 62% were males, 91% were white, and 86% were non-Hispanics. OS was significantly improved in overweight and obese compared to normal BMI patients (HR 0.72, 95% CI, 0.60-0.86; P &lt; 0.001, and HR 0.53, 95% CI, 0.43-0.65); P &lt; 0.001, respectively). Nearly one-third of all weight categories had an irAE. Skin toxicity was the most common, 16.5%-18.2%, while pneumonitis was the least common, 1.0% -2.0%. There was no statistically significant difference between the groups in all included irAE; skin toxicities, thyroid dysfunction, colitis, pneumonitis, or hepatitis. Conclusions: This is the largest real-world data study describing the association between weight status and the outcomes of ICI in melanoma. Our study showed that overweight and obese melanoma patients treated with single or combination ICI had a significantly improved OS compared to patients with normal BMI, in keeping with the “obesity paradox” phenomenon. Intriguingly, high BMI wasn’t associated with an increased risk of irAE. Studies to clarify the underlying mechanisms in melanoma and other malignancies are needed. [Table: see text]
T cell redirecting and TLR7/8 agonist encapsulated liposomes targeting HER2+ tumors: Preclinical efficacy, pharmacokinetics and safety evaluations.
Authors: Anjie Zheng, Shanshan Jin, Shuhang Wang, Xuan Wu, Danting Xie, Jinfeng Long, Yongchao Dai, Fengwei Xu, Ning Li, Yuhong Xu
Journal: Journal of Clinical Oncology (2023)

e14590 Background: T-cell dependent bispecific antibodies (TDBs) have shown limited success in solid tumor treatments. We hypothesized that it may be due to TDBs limited distribution in solid tumor tissues. We therefore propose to take advantage of the EPR (enhanced permeability and retention) effect of the liposome system to improve the PKPD properties of TDBs. The liposomes are named TRAFsomes (T cell Redirecting Antibody Fragment-anchored Liposomes). HF5050 is a TRAFsome containing on average 6 anti-CD3 and 10 anti-Her2 on each liposome surface and the toll-like TLR-7/8 agonist Resiquimod encapsulated inside at specific lipid to drug ratios. It preclinical efficacy, pharmacokinetics and safety evaluation studies are conducted to support the IND application. Methods: The T cell redirecting and target specific cytotoxic effect of HF5050 were evaluated in five PBMC co-cultured cancer cell models with different Her2 expression. Tumor cells derived from adenoid cystic carcinoma tumor tissues was also included. T cell redirection and activation are examined by T cell surface markers CD25/CD69 and secretion of IFN gamma, Perforin, and granzymes B in the absence and presence of cancer cells. For the incorporation of TLR7/8 agonist Resiquimod, we evaluated the effect of drug dose by varying the drug loading ratios in order to achieve a synergistic effect. For the in vivo efficacy studies, the N87 gastric cancer CDX model and an adenoid cystic carcinoma tumor PDX model were set on PBMC reconstructed humanized NCG-B2M mice. Pharmacokinetic and tissue distribution studies are carried out in tumor bearing mouse models as well. Results: HF5050 has shown to be a highly effective anti-cancer agent in both in vitro and in vivo studies. It mediates T cells-tumor cells redirection and cytotoxicity in a dose-dependent manner, especially in Her-2 highly expressing cell lines. HF5050 also effectively stimulates T cell activation and displays high efficacy in PBMC reconstruct humanized NCG-B2M tumor-bearing mice. Pharmacokinetic research confirms liposome successfully maintains drug levels in the bloodstream, and improves drug accumulation within tumor tissues. Conclusions: Overall, these data demonstrate that HF5050 processing a novel cell bridging function between T cells and tumor cells, and with the capability of activating immune cells. Based on the encouraging preclinical results, HF5050 exhibits promising development potential.
Distinguishing between cancer-related mutations and clonal hematopoiesis using cell-free RNA (cfRNA) expression levels in a machine learning model.
Authors: Maher Albitar, Hong Zhang, Andrew Ip, Jeffrey Estella, Ahmad Charifa, Wanlong Ma, Arash Mohtashamian, Martin Gutierrez, Andrew L Pecora, Andre Goy
Journal: Journal of Clinical Oncology (2023)

3043 Background: Liquid biopsy is currently considered an important part of the clinical practice of oncology. However, proper interpretation of somatic mutations detected in liquid biopsy remains a challenge. Distinguishing cancer-related mutations from mutations resulting from clonal hematopoiesis of indeterminate potential (CHIP) can be difficult and a source of misinterpretation of liquid biopsy findings. We explored using cell-free RNA (cfRNA) profiling as a means for distinguishing between mutations detected as CHIP vs mutations detected as cancer. Methods: cfDNA and cfRNA from 102 patients with confirmed solid tumors, 93 patients with hematologic neoplasms and 40 patients with CHIP abnormalities were sequenced using a panel of 1501 gene for RNA and 284 genes for DNA. The solid tumors included lung, breast, ovarian, and colorectal. The hematologic neoplasms included lymphoid and myeloid neoplasms. Using a machine learning algorithm, we first selected the relative genes that distinguish between two classes using K-fold cross-validation (K=12). The selected genes were used to predict one class from the other using naïve Bayesian classifier, but we applied geometric mean naïve Bayesian (GMNB) to compensate for the expected underflow. Results: Using machine learning with cfRNA, we were able to distinguish between cases with confirmed cancer-related mutations and CHIP mutations with area under the curve (AUC) of 0.808 (95% CI: 0.720-0.895). Precision, recall and f1-score were 0.86, 0.422 and 0.566 for CHIP and 0.359, 0.825 and 0.500 for solid tumor, respectively. The machine learning required 70 genes for this classification. Leave-one-out (LOO) validation showed AUC of 0.766 (95% CI: 0.671-0.859). Distinguishing between hematologic neoplasms and CHIP was achievable using the expression of 30 genes. The AUC for this model was 0.787 (95% CI: 0.696-0.879). Precision, recall and f1-score were 0.906, 0.516, and 0.658 for CHIP and 0.438, 0.875, and 0.583 for hematologic neoplasms, respectively. Validation using LOO showed AUC of 0.736 (95% CI : 0.638-0.835). The top 10 genes that their expression was critical for distinguishing between CHIP and solid tumors were EIF4E, HNF1A, HOOK3, HIPK2, IL1RAP, BRAF, DNAJB1, GADD45B, H2AX, and HDAC6. The top 10 genes for distinguishing hematologic cancers from CHIP were PBX1, CAMTA1, PFDN5, PCBP1, SDC4, PRKACA, NT5C2, NBR1, RPS21, and AHCYL1. Conclusions: Analyzing cfRNA expression levels when used with machine learning may add another level of confidence to the ability of interpreting mutations detected in liquid biopsy testing, especially when these mutations are at low levels. This is particularly important in liquid biopsy testing for minimal residual disease (MRD) when a tissue baseline sample is not tested (tumor-agnostic).
Are severe immune-related adverse events more likely in patients with pre-existing autoimmune disease?
Authors: Dayna Jill Isaacs, Robin Hilder, Alexandra Drakaki, Melissa G Lechner
Journal: Journal of Clinical Oncology (2023)

e14599 Background: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that activate the immune system to treat malignancy. As a consequence of this activation, ICIs may cause autoimmunity in healthy tissues, termed “immune-related Adverse Events” (irAEs). The literature reports a wide range in irAE incidence (10-80%), with a higher incidence in patients exposed to combination therapy. ICI treatment of patients with pre-existing autoimmune disease presents a dilemma for oncologists because of concern that immune activation will lead to more frequent or severe irAEs. As a result, these patients have been excluded from ICI clinical trials. Prior studies suggested that approximately 40% of patients with pre-existing autoimmune disease experience an autoimmune exacerbation during ICI treatment, but more data are needed on the incidence and severity of irAEs in other tissues. Methods: This retrospective case-control study included adult patients who received an FDA-approved ICI for treatment of a solid malignancy (excluding non-melanoma skin cancer) from 2015-2021 at an academic medical center. Cases were patients with pre-existing autoimmune disease. Controls without pre-existing autoimmunity were matched 2:1 based on age, sex, ICI class, and cancer type. Severe IrAEs were defined as grade three or higher by CTCAE definitions and occurring after ICI exposure. ICD-9 and 10 codes were used to identify patients with subsequent data extraction by manual chart review. Results: Of 3,130 adult cancer patients treated with ICIs, 28 cases were identified with pre-existing autoimmune disease: antiphospholipid syndrome (n=1), inflammatory polyarthritis (n=3), juvenile arthritis (n=1), multiple sclerosis (n=3), psoriatic arthritis (n=3), rheumatoid arthritis (n=14), and type I diabetes (n=3). Six out of 28 cases (21.4%) developed severe irAEs, including three (50%) who received anti-PD1/PDL1 monotherapy and three (50%) who received ICI combination therapy. One case experienced a grade five irAE (death) attributed to ICI-colitis; the remaining five patients (83.3%) successfully recovered with suspension of ICI therapy and treatment with immunosuppressive medications. By comparison, 9/56 (16.1%) controls developed severe irAEs. The odds of developing a severe irAE were not significantly different in patients with pre-existing autoimmunity compared to controls (OR 1.42, 95% CI 0.42-4.68, p=ns). Subgroup analysis of 23 cases and 46 controls treated with anti-PD1/PDL1 monotherapy also found no difference in the odds of severe irAE development (OR 0.84, 0.22-3.70, p=ns). Conclusions: Our data suggest that the majority of solid tumor patients with pre-existing autoimmune disease can safely receive ICI monotherapy and combination therapy. Severe (grade 3 or higher) irAEs were infrequent, often treatable, and did not occur more frequently than in patients without pre-existing autoimmunity.
Phase 3 TRIDENT study (EF-32): Tumor treating fields (TTFields; 200 kHz) concomitant with chemoradiation, and maintenance TTFields therapy/temozolomide in newly diagnosed glioblastoma.
Authors: Wenyin Shi, David Roberge, Lawrence Kleinberg, Suriya A. Jeyapalan, Samuel Aaron Goldlust, Seema Nagpal, Leonardo Lustgarten, Stephanie E Combs, Ryo Nishikawa, David A. Reardon, Rachel Grossman, Martin Glas
Journal: Journal of Clinical Oncology (2023)

TPS2083 Background: Tumor Treating Fields (TTFields) therapy, a noninvasive and locoregional antimitotic cancer treatment modality, is approved for newly diagnosed (nd), recurrent glioblastoma (r) GBM and mesothelioma. In patients with ndGBM, progression-free survival (PFS) and overall survival (OS) were significantly improved with TTFields therapy/temozolomide (TMZ) vs TMZ alone in the pivotal EF-14 study, leading to FDA approval in ndGBM. To avoid potential impedance of radiotherapy (RT), TTFields therapy was administered following RT/TMZ; however, preclinical studies have demonstrated that TTFields therapy enhances the therapeutic effect of RT. Methods: TRIDENT (EF-32; NCT04471844), a phase 3, global, randomized study, will evaluate TTFields therapy concomitant with RT/TMZ in patients ≥18 years of age (≥22 years in the US) with histologically-confirmed ndGBM, ≥3 months life expectancy, and ≥70 Karnofsky performance status. Patients will be stratified on the basis of MGMT promoter methylation status and extent of resections. Approximately 950 patients will be assigned 1:1 to continuous TTFields therapy (200 KHz, ≥18 h/day) concomitant with RT/TMZ (experimental arm) or RT/TMZ alone (control arm). Patients in the experimental arm will receive TTFields therapy continuously from the first day of chemoradiation. Patients in the control group will begin TTFields at the same time as maintenance TMZ, approximately one month after completion of chemoradiation. TTFields therapy will continue in both treatment groups until second disease progression (PFS2) or 24 months (if clinically able). The primary endpoint is median OS, and secondary endpoints include PFS, 1- and 2-year survival rates, objective response rate, PFS2, 6- and 12-month PFS rates, safety, and quality of life (EORTC QoL questionnaires). The ability of TTFields therapy to extend OS in a dose-dependent manner is an exploratory endpoint. The sample size is powered for a hazard ratio of &lt; 0.8 with a 5% type I error. The hypothesis that first-line TTFields therapy/RT/TMZ can significantly improve OS vs RT/TMZ will be tested using a stratified log-rank test. The study is expected to enroll patients at 150 sites, with enrollment currently open in 9 countries. Clinical trial information: NCT04471844 .
Prostate-specific membrane antigen ligand positron emission tomography (PSMA-PET) disease extent and overall survival (OS) in patients (pts) with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC): An international multicenter retrospective study.
Authors: Boris A. Hadaschik, Matthias Eiber, Manuel Weber, Aravind Ravi Kumar, Jeremie Calais, Johannes Czernin, Harun Ilhan, Fred Saad, Alexander Kretschmer, Sabine D. Brookman-May, Suneel Mundle, Eric Jay Small, Matthew Raymond Smith, Paola M. Perez Rivera, Thomas A. Hope, Ken Herrmann, Michael S Hofman, Wolfgang P. Fendler
Journal: Journal of Clinical Oncology (2023)

5010 Background: PSMA-PET was positive for distant metastases (39% distant nodes, 24% bone, 6% visceral organ) in &gt;50% of nmCRPC pts who were nonmetastatic by conventional imaging (Fendler et al. CCR 2019). However, the prognostic impact of PSMA-PET disease extent and its association with oncologic outcomes is unknown. We assessed the prognostic utility of PSMA-PET disease extent in nmCRPC pts defined by conventional imaging for OS and new metastases-free survival (nMFS). Methods: 200 pts (6 centers) with nmCRPC by conventional imaging and prostate-specific antigen doubling time (PSADT) ≤10 mo and/or ISUP grade group ≥4 underwent PSMA-PET. Clinical course and treatment management after PSMA-PET imaging were recorded for 4-9 y. Pt characteristics and PSMA-PET disease extent were analyzed retrospectively. OS and PSMA-PET nMFS (time from primary PSMA-PET to appearance of new distant metastases by PSMA-PET or death) were analyzed for pt subgroups based on disease extent by univariate Cox regression. Results: Median OS was 74 mo, similar to the SPARTAN study of nmCRPC pts (74 mo; Smith et al. Eur Urol 2021). Polymetastatic disease (≥5 distant lesions by PSMA-PET) was associated with shorter OS (median 61 mo vs not reached [NR]) and shorter PSMA-PET nMFS (HR 1.8, 95% CI 1.1-2.9; median 38 vs 60 mo; p=0.021). Any metastatic disease by PSMA-PET and whole-body PSMA tumor volume were not prognostic for OS and PSMA-PET nMFS (all p&gt;0.05). Initial pN1 status was associated with shorter OS (median 55 mo vs NR), but not with PSMA-PET nMFS (p&gt;0.05). Baseline age, baseline Gleason grade ≥8, prior radiotherapy (RT), and PSA and PSADT at time of primary PSMA-PET were not associated with outcomes (all p&gt;0.05). Management after PSMA-PET imaging was mostly local/targeted therapy in pts with no visible/locoregional disease (40/30%) and androgen receptor signaling inhibition therapy in pts with nodal/bone distant metastases (35/43%). Conclusions: Polymetastases (&gt;5) by PSMA-PET and initial pN1 status were significantly associated with worse OS. PSMA-PET disease extent provides a potential novel additional risk stratification for pts with nmCRPC without distant metastasis based on conventional imaging. Further validation is needed to prove its independent prognostic value. Clinical trial information: NCT01946204 . [Table: see text]